Hungyuan B. Liu

Boron neutron capture therapy for glioblastoma multiforme using p-boronophenylalanine and epithermal neutrons: trial design and early clinical results.

A Phase I/II clinical trial of boron neutroncapture therapy (BNCT) for glioblastoma multiforme is underwayusing the amino acid analog p-boronophenylalanine (BPA) andthe epithermal neutron beam at the Brookhaven MedicalResearch Reactor. Biodistribution studies were carried out in18 patients at the time of craniotomy usingan i.v. infusion of BPA, solubilized as afructose complex (BPA-F). There were no toxic effectsrelated to the BPA-F administration at doses of130, 170, 210, or 250 mg BPA/kg bodyweight. The tumor/blood, brain/blood and scalp/blood boron concentrationratios were approximately 3.5:1, 1:1 and 1.5:1, respectively.Ten patients have received BNCT following 2-hr infusionsof 250 mg BPA/kg body weight. The averageboron concentration in the blood during the irradiationwas 13.0 ± 1.5 μg 10B/g. The prescribedmaximum dose to normal brain (1 cm3 volume)was 10.5 photon-equivalent Gy (Gy-Eq). Estimated maximum andminimum doses (mean ± sd, n=10)to the tumor volume were 52.6 ± 4.9Gy-Eq (range: 64.4–47.6) and 25.2 ± 4.2 Gy-Eq(range: 32.3–20.0), respectively). The estimated minimum dose tothe target volume (tumor + 2 cm margin)was 12.3 ± 2.7 Gy-Eq (range: 16.2–7.8). Therewere no adverse effects on normal brain. Thescalp showed mild erythema, followed by epilation inthe 8 cm diameter field. Four patients developedrecurrent tumor, apparently in the lower dose (deeper)regions of the target volume, at post-BNCT intervalsof 7, 5, 3.5 and 3 months, respectively.The remaining patients have had less than 4months of post-BNCT follow-up. BNCT, at this startingdose level, appears safe. Plans are underway tobegin the dose escalation phase of this protocol.

Neutron capture therapy of the 9l rat gliosarcoma using the P-boronophenylalanine-fructose complex

PURPOSE Intraperitoneal (IP) injection of the solubilized fructose complex of L-p-boronophenylalanine (BPA-F) produced higher boron concentrations in a rat brain tumor model than was possible using intragastric (IG) administration of L-p-boronophenylalanine (BPA). The effectiveness of IP BPA-F was compared to IG BPA in boron neutron capture therapy irradiations of the 9L rat brain tumor model. METHODS AND MATERIALS The time course of boron accumulation in tumor and normal tissues was determined in male F344 rats bearing either SC or intracerebral 9L gliosarcomas following a single IP injection of BPA-F. On day 14 after inoculation of intracranial tumors, rats were irradiated with single doses of either: 250 kVp X rays; the thermal neutron beam of the Brookhaven Medical Research Reactor following IG administration of BPA; or thermal neutrons following IP injection of BPA-F. Magnetic resonance imaging was used to visualize the tumor scars and to assess damage to the normal brain in long-term survivors. RESULTS 4 h after IP injection of 1200 mg/kg of BPA-F the boron concentrations in tumor, blood, and normal brain were 89.6 +/- 7.6, 27.7 +/- 2.8 and 17.5 +/- 1.5 micrograms 10B/g, respectively. Two IG doses of BPA (750 mg/kg each, 3 h apart) produced 39 +/- 5, 12 +/- 1 and 10 +/- 1 micrograms 10B/g in tumor, blood and brain, respectively at 5 h after the second dose. Three groups of rats were treated with thermal neutrons: one following IG BPA and two groups following IP BPA-F. The total physical absorbed doses to the tumor in the three BNCT groups were 15.5 Gy (IG BPA, n = 12), 17.0 Gy (IP BPA-F, n = 8), and 31.5 Gy (IP BPA-F, n = 8), respectively. The median survival of the untreated controls was 22 days. The median survival of the rats treated with 22.5 Gy of 250 kVp X rays (n = 23) was 35 days with 20% long-term survivors. Fifty percent of the rats in the IG BPA + thermal neutrons group survived over 1 year. All rats in both groups that received IP BPA-F + thermal neutrons have survived over 8 months. Magnetic resonance imaging of the brains of the long-term boron neutron capture therapy survivors showed a scar at the site of tumor implantation in all animals. In the IP BPA-F high-dose group one rat showed evidence of edema and one rat showed a fluid-filled cyst replacing the tumor. CONCLUSION The use of IP BPA-F has significantly improved long-term survival compared to IG BPA. The high percentage of long-term tumor control (100%, n = 16) in the intracerebral rat 9L gliosarcoma brain tumor model, together with little or no damage to the surrounding normal brain in the majority of surviving animals, demonstrate the substantial therapeutic gain produced by boron neutron capture therapy.

Boron Neutron-Capture Therapy (BNCT) for Glioblastoma Multiforme (GBM) Using the Epithermal Neutron Beam at the Brookhaven National Laboratory

OBJECTIVE Boron neutron-capture therapy (BNCT) is a binary form of radiation therapy based on the nuclear reactions that occur when boron (10B) is exposed to thermal neutrons. Preclinical studies have demonstrated the therapeutic efficacy of p-boronophenylalanine (BPA)-based BNCT. The objectives of the Phase I/II trial were to study the feasibility and safety of single-fraction BNCT in patients with GBM. MATERIALS AND METHODS The trial design required (a) a BPA biodistribution study performed at the time of craniotomy; and (b) BNCT within approximately 4 weeks of the biodistribution study. From September 1994 to July 1995, 10 patients were treated. For biodistribution, patients received a 2-hour intravenous (i.v.) infusion of BPA-fructose complex (BPA-F). Blood samples, taken during and after infusion, and multiple tissue samples collected during surgical debulking were analyzed for 10B concentration. For BNCT, all patients received a dose of 250 mg BPA/kg administered by a 2-hour i.v. infusion of BPA-F, followed by neutron beam irradiation at the Brookhaven Medical Research Reactor (BMRR). The average blood 10B concentrations measured before and during treatment were used to calculate the time of reactor irradiation that would deliver the prescribed dose. RESULTS 10B concentrations in specimens of scalp and tumor were higher than in blood by factors of approximately 1.5 and approximately 3.5, respectively. The 10B concentration in the normal brain was < or = that in the blood; however, for purposes of estimating radiation doses to normal brain endothelium, it was always assumed to be equal to blood. BNCT doses are expressed as gray-equivalent (Gy-Eq), which is the sum of the various physical dose components multiplied to appropriate biologic effectiveness factors. The dose to a 1-cm3 volume where the thermal flux reached a maximum was 10.6 +/- 0.3 Gy-Eq in 9 patients and 13.8 Gy-Eq in 1 patient. The minimum dose in tumor ranged from 20 to 32.3 Gy-Eq. The minimum dose in the target volume (tumor plus 2 cm margin) ranged from 7.8 to 16.2 Gy-Eq. Dose to scalp ranged from 10 to 16 Gy-Eq. All patients experienced in-field alopecia. No CNS toxicity attributed to BNCT was observed. The median time to local disease progression following BNCT was 6 months (range 2.7 to 9.0). The median time to local disease progression was longer in patients who received a higher tumor dose. The median survival time from diagnosis was 13.5 months. CONCLUSION It is feasible to safely deliver a single fraction of BPA-based BNCT. At the dose prescribed, the patients did not experience any morbidity. To further evaluate the therapeutic efficacy of BNCT, a dose-escalation study delivering a minimum target volume dose of 17 Gy-Eq is in progress.

An improved neutron collimator for brain tumor irradiations in clinical boron neutron capture therapy

To improve beam penetration into a head allowing the treatment of deeper seated tumors, two neutron collimators were built sequentially and tested for use in the clinical boron neutron capture therapy (BNCT) program at the epithermal neutron irradiation facility of the Brookhaven Medical Research Reactor. The collimators were constructed from lithium-impregnated polyethylene, which comprises Li2CO3 powder (approximately 93% enriched isotopic 6Li) uniformly dispersed in polyethylene to a total 6Li content of 7.0 wt. %. The first collimator is 7.6 cm thick with a conical cavity 16 cm in diameter on the reactor core side tapering to 8 cm facing the patients head. The second collimator is 15.2 cm thick with a conical cavity 20 cm in diameter tapering to 12 cm. A clinical trial of BNCT for patients with malignant brain tumors is underway using the first collimator. Results of phantom dosimetry and Monte Carlo computations indicate that the new 15.2 cm thick collimator will improve the neutron beam penetration. Thus, the second collimator was made and will be used in an upcoming clinical trial. In-air and in-phantom mixed-field dosimetric measurements were compared to Monte Carlo computations for both collimators. The deeper penetration is achieved but at a sacrifice in beam intensity. In this report, a performance comparison of both collimators regarding various fluence rate and absorbed dose distributions in a head model is presented and discussed.

The Requirements and Development of Neutron Beams for Neutron Capture Therapy of Brain Cancer

One of the two overriding conditions for successfulBNCT is that there must be a sufficientnumber of thermal neutrons delivered to each ofthe boronated cells in the tumour bed (targetvolume). Despite the poor experience with BNCT inthe USA some 40 years ago, the continuedapparent success of BNCT in Japan since 1968,lead indirectly to the re-start of clinical trialson BNCT in 1994 at both Brookhaven andMIT. Similar trials will start soon at Pettenin Europe. At other centres worldwide, many neutronbeam designs are being proposed with either thermalor epithermal neutrons, emanating predominately from nuclear researchreactors. It is apparent that whilst the successof BNCT depends on a suitable neutron beam,there is a diversity in available designs, aswell as each proposed type of neutron source,with consequently different characteristics of the emergent neutronbeam. The paper presents the historical development ofneutron beams used for BNCT, addresses the requirementson the types of beams, describes some ofthe existing designs and other proposals elsewhere andlastly, considers the broader requirements in designing NCTfacilities. The focus of the paper is ontreatment of brain cancer, neutron beam requirements forother types of cancer may vary.

Enhancement of the epithermal neutron beam used for boron neutron capture therapy

PURPOSE This report describes a study to enhance the epithermal neutron beam at the Brookhaven Medical Research Reactor by increasing the epithermal neutron flux and/or reducing contamination by fast neutrons. METHODS AND MATERIALS The beam was reevaluated using Monte Carlo calculations and flux and dose measurements in air and in an ellipsoidal head phantom at the patient irradiation port. Changes in its geometry and materials were considered, including rearranging the fuel elements in the reactor core and redesigning the moderator and the patient irradiation port. RESULTS Calculations of the new fluxes and doses at the patient irradiation port showed that the epithermal neutron flux can be increased by 100%, while the fast neutron dose per epithermal neutron can be reduced by 38%. In 1992, some of the proposed changes were made. In June 1992, measurements were made after one additional fuel element was added to replace a graphite spacer block on the epithermal beam side of the reactor core. The results show that the epithermal neutron flux increased by 18%, as predicted by the Monte Carlo calculations. In October 1992, the fuel elements in the reactor core were rearranged by placing four new fuel elements in the first row facing the epithermal port; the intensity of the epithermal neutron beam increased by 50% and the fast neutron and gamma doses per epithermal neutron may have decreased slightly. CONCLUSION The epithermal neutron beam at the Brookhaven Medical Research Reactor has gained a 50% increase in the epithermal neutron flux and the fast neutron and gamma doses per epithermal neutron are reduced slightly after the rearrangement of the fuel elements in the core.

Design of a high‐flux epithermal neutron beam using 235U fission plates at the Brookhaven Medical Research Reactor

Beams of epithermal neutrons are being used in the development of boron neutron capture therapy for cancer. This report describes a design study in which 235U fission plates and moderators are used to produce an epithermal neutron beam with higher intensity and better quality than the beam currently in use at the Brookhaven Medical Research Reactor (BMRR). Monte Carlo calculations are used to predict the neutron and gamma fluxes and absorbed doses produced by the proposed design. Neutron flux measurements at the present epithermal treatment facility (ETF) were made to verify and compare with the computed results where feasible. The calculations indicate that an epithermal neutron beam produced by a fission-plate converter could have an epithermal neutron intensity of 1.2 x 10(10) n/cm2.s and a fast neutron dose per epithermal neutron of 2.8 x 10(-11) cGy.cm2/nepi plus being forward directed. This beam would be built into the beam shutter of the ETF at the BMRR. The feasibility of remodeling the facility is discussed.

Improved apparatus for neutron capture therapy of rat brain tumors

PURPOSE The assembly for irradiating tumors in the rat brain at the thermal neutron beam port of the Brookhaven Medical Research Reactor was redesigned to lower the average whole-body dose from different components of concomitant radiation without changing the thermal neutron fluence at the brain tumor. METHODS AND MATERIALS At present, the tumor-bearing rat is positioned in a rat holder that functions as a whole-body radiation shield. A 2.54 cm-thick collimator with a centered conical aperture, 6 cm diameter tapering to 2 cm diameter, is used to restrict the size of the thermal neutron field. Using the present holder and collimator as a baseline design, Monte Carlo calculations and mixed-field dosimetry were used to assess new designs. RESULTS The computations indicate that a 0.5 cm-thick plate, made of 6Li2CO3 dispersed in polyethylene (Li-poly), instead of the existing rat holder, will reduce the whole-body radiation dose. Other computations show that a 10.16 cm-thick (4 inches) Li-poly collimator, having a centered conical aperture of 12 cm diameter tapering to 2 cm diameter, would further reduce the whole-body dose. CONCLUSION The proposed irradiation apparatus of tumors in the rat brain, although requiring a 2.3-fold longer irradiation time, would reduce the average whole-body dose to less than half of that from the existing irradiation assembly.

Boron Neutron Capture Therapy of Glioblastoma Multiforme Using the p-Boronophenylalanine-Fructose Complex and Epithermal Neutrons

The amino acid analogue p-boronophenylalanine (BPA) is under investigation as a neutron capture agent for BNCT of glioblastoma multiforme. A series of patients undergoing surgical removal of tumor received BPA orally as the free amino acid. Favorable tumor/blood boron concentration ratios were obtained but the absolute amount of boron in the tumor would have been insufficient for BNCT. BPA can be solubilized at neutral pH by complexation with fructose (BPA-F). Studies with rats suggest that intraperitoneal injection of BPA-F complex produces a much higher tumor boron concentration to rat intracerebral 9L gliosarcoma that were possible with oral BPA. Higher boron concentrations have allowed higher tumor radiation doses to be delivered while maintaining the dose to the normal brain vascular endothelium below the threshold of tolerance. The experience to date of the administration of BPA-F to one patient is provided in this report.

Calibration of the delayed‐gamma neutron activation facility

The delayed-gamma neutron activation facility at Brookhaven National Laboratory was originally calibrated using an anthropomorphic hollow phantom filled with solutions containing predetermined amounts of Ca. However, 99% of the total Ca in the human body is not homogeneously distributed but contained within the skeleton. Recently, an artificial skeleton was designed, constructed, and placed in a bottle phantom to better represent the Ca distribution in the human body. Neutron activation measurements of an anthropomorphic and a bottle (with no skeleton) phantom demonstrate that the difference in size and shape between the two phantoms changes the total body calcium results by less than 1%. To test the artificial skeleton, two small polyethylene jerry-can phantoms were made, one with a femur from a cadaver and one with an artificial bone in exactly the same geometry. The femur was ashed following the neutron activation measurements for chemical analysis of Ca. Results indicate that the artificial bone closely simulates the real bone in neutron activation analysis and provides accurate calibration for Ca measurements. Therefore, the calibration of the delayed-gamma neutron activation system is now based on the new bottle phantom containing an artificial skeleton. This change has improved the accuracy of measurement for total body calcium. Also, the simple geometry of this phantom and the artificial skeleton allows us to simulate the neutron activation process using a Monte Carlo code, which enables us to calibrate the system for human subjects larger and smaller than the phantoms used as standards.